German David M, Mitalipov Shoukhrat, Mishra Anusha, Kaul Sanjiv
Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon.
Center for Embryonic Cell and Gene Therapy, Oregon Health and Science University, Portland, Oregon.
JACC Basic Transl Sci. 2019 Feb 25;4(1):122-131. doi: 10.1016/j.jacbts.2018.11.004. eCollection 2019 Feb.
A variety of genetic cardiovascular diseases may one day be curable using gene editing technology. Germline genome editing and correction promises to permanently remove monogenic cardiovascular disorders from the offspring and subsequent generations of affected families. Although technically feasible and likely to be ready for implementation in humans in the near future, this approach remains ethically controversial. Although currently beset by several technical challenges, and not yet past small animal models, somatic genome editing may also be useful for a variety of cardiovascular disorders. It potentially avoids ethical concerns about permanent editing of the germline and allows treatment of already diseased individuals. If technical challenges of Cas9-gRNA delivery (viral vector immune response, nonviral vector delivery) can be worked out, then CRISPR-Cas9 may have a significant place in the treatment of a wide variety of disorders in which partial or complete gene knockout is desired. However, CRISPR may not work for gene correction in the human heart because of low rates of homology directed repair. Off-target effects also remain a concern, although, thus far, small animal studies have been reassuring. Some of the therapies mentioned in this review may be ready for small clinical trials in the near future.
未来某一天，利用基因编辑技术或许可以治愈多种遗传性心血管疾病。生殖系基因组编辑和校正有望从受影响家庭的后代及后续世代中永久消除单基因心血管疾病。尽管在技术上可行且可能在不久的将来就准备好在人体中实施，但这种方法在伦理上仍存在争议。尽管目前受到若干技术挑战的困扰，且尚未超越小动物模型阶段，但体细胞基因组编辑对于多种心血管疾病可能也有用处。它有可能避免对生殖系进行永久编辑所引发的伦理问题，并允许对已经患病的个体进行治疗。如果能够解决Cas9-gRNA递送的技术挑战（病毒载体免疫反应、非病毒载体递送），那么CRISPR-Cas9在治疗各种需要部分或完全基因敲除的疾病中可能会占据重要地位。然而，由于同源定向修复率较低，CRISPR可能对人类心脏中的基因校正不起作用。脱靶效应仍然是一个问题，不过到目前为止，小动物研究的结果令人安心。本综述中提到的一些疗法可能在不久的将来就准备好进行小型临床试验。
